Cardiac chronotropic incompetence is associated with increased morbidity and mortality (1-3). The majority of cases of symptomatic chronotropic incompetence are treated by implantation of a permanent electronic pacemaker.
Pacemaker responsiveness is one of the most recent developments in pacemaking technology. Designed to allow the pacemaker to meet the physiologic needs of the individual, pacemaker response elements are most clinically applicable in cases of chronotropic incompetence. Responsive elements are biosensors of physiologic demand, commonly measuring O2, temperature or movement as surrogates of input signals which direct endogenous cardiac chronotropic activity. Unfortunately, while the development of pacemaker responsiveness has improved the exercise tolerance of patients as compared to treatments with pacemakers without responsive elements (4), the potential of this approach has not yet been fulfilled (5, 6). Previous studies have demonstrated that when directly compared to the endogenous sinus nodal activity, pacemaker responsive elements may have only a 70% correlation with endogenous activity (7, 8). Moreover, inappropriate chronotropic responsiveness can contribute to diminished exercise tolerance and fatigue, and less commonly but more importantly, such dysregulation may lead to inappropriate tachycardias (9).
Advances in pacemaker responsiveness have focused both on improving the integration of the acquired sensory data and on employing the endogenous myocardium into the biosensory circuits. Studies have demonstrated that sophisticated programming with intensive complex or individualized programming may facilitate the blending of multiple sensory inputs in order to improve individual chronotropic regulation to enhance exercise performance (10-12). An alternative approach in chronotropic responsiveness research has been to attempt to exploit the chronotropic regulatory capacity of the endogenous cardiac myocardium. Pacemaking biosensors are being tested and developed to incorporate direct cardiac myocardial signals into the regulation of pacemaking including inputs of cardiac contractility (13), and QT intervals (14-16). Recently, neural network computer programs have been developed based on the morphology of intracardiac electrograms in an attempt to xe2x80x98learnxe2x80x99 physiologic sensing (17). While the integration of direct cardiac inputs may have advantages over the more common measurements of surrogate markers of physiologic demand, this approach relies on the sensing of pathologic tissue: the chronotropically incompetent heart. Indeed, the diversity of the primary or secondary disease processes underlying chronotropic incompetence often affects other components of the cardiac conduction system (18, 19), as well as myocardium (3). Hence, this associated pathology may significantly impair the ability of the endogenous heart to function as an accurate biosensor and transducer element for the prediction of heart rate.
Dynamic regulation of biological systems requires real-time assessment of relevant physiological needs. Biosensors, which transduce biological actions or reactions into signals amenable to processing, are well-suited for such monitoring. Typically, in vivo biosensors approximate physiological function via the measurement of surrogate signals. Biosensors derive utility from their inherent selectivity to specific biological signals and their physiologically relevant reactions [20]. Most biosensors are molecularly based, relying on a specific interaction between biomolecules such as antibodies [22, 22], enzymes [23, 24], ion channels [25, 26], or nucleic acids [20, 27, 28] and a target compound. Alternatively, cell-and tissue-based biosensors [29-31 ] offer inherent insight into physiological function by exploiting the selectivity of the receptors, channels, and enzymes that are part of the cell""s functional structure. Most cell-and tissue-based biosensors are used for chemical detectionxe2x80x94a task for which they are quite adept, but not one for which they specifically evolved.
The present invention employs the inherent biosensing capacity of excitable tissue in a healthy state. The present invention thus provides biologically-based biosensors for the direct measurement of physiological activity via functional integration of relevant governing inputs. The subject biosensors may be used to monitor physiological function and even replace or augment degraded sensing function of endogenous tissue. When implanted, the subject biosensors may be used as real-time, integrated bioprocessors of the complex inputs regulating dynamic physiological variables. The biosensors of the present invention provide biologically-tuned quantification of remote physiological function, and are therefore useful as exogenous electropotential interfaces for external or implantable devices.
The present invention provides implantable physiological or pathophysiological biosensors. The subject biosensors comprise tissue or cells capable of carrying out a physiological or pathophysiological function, which can be used to monitor a chemical, physiological or pathophysiological variable associated with the physiological or pathophysiological function. In one embodiment, the tissue or cells are coupled via an electrical interface to an electronic measuring device or an electronic amplifying device. In another embodiment, the tissue or cells are coupled via an electrical interface to endogenous tissue or cells, including the blood. Preferably, the tissue or cells are excitable tissue or cells. Examples of excitable tissue or cells include cardiac tissue or cells and neuronal tissue or cells.
The tissue or cells of a subject biosensor may be molecularly, genetically, or cellularly engineered. A physiological or pathophysiological variable monitored by the biosensor of the present invention may include, for example, heart rate regulation or heart rate dynamics. Another chemical, physiological or pathophysiological variable which may be monitored by a biosensor of the present invention is a level of a compound. Examples of such compounds include but are not limited to blood glucose, insulin, thyroid hormone, clotting factors and components, endocrine hormone, paracrine hormone, autocrine hormone, antibodies, receptor antagonists, ligands, antigens, antagonists, signal pathway cofactors, signal pathway components, pathogens, drugs, metabolites and toxins.
In accordance with the present invention, a subject biosensor may be implanted or inserted in an animal. Preferably, the animal is a mammal. Examples of mammals into which a subject biosensor may be implanted include but are not limited to a mouse, rat, rabbit, pig, cat, dog, cattle, horse or sheep. Most preferably, the mammal is human.
The present invention also provides a method for monitoring physiological or pathophysiological function. The method comprises placing into a subject, tissue or cells capable of carrying out a physiological or pathophysiological function within the subject, which tissue or cells can be used to monitor a chemical, physiological or pathophysiological variable associated with the physiological or pathophysiological function of the subject. The exogenous tissue or cells are then monitored for physiological or pathophysiological function. Preferably, tissue or cells for use in the method comprise excitable tissue or cells. Examples of excitable tissue or cells for use in the method include cardiac tissue or cells, and neuronal tissue or cells.
In the method for monitoring a physiological or pathophysiological function, the tissue or cells used for placement into a subject may be coupled via an electrical interface to an electronic measuring device. The tissue or cells may also be coupled via an electrical interface to endogenous tissue or cells. Examples of physiological or pathophysiological variables which may be measured according to the method include heart rate regulation or heart rate. Also in accordance with the method, a chemical, physiological or pathophysiological variable may be a level of a compound such as e.g., blood glucose, insulin, thyroid hormone, clotting factors and components, endocrine hormone, paracrine hormone, autocrine hormone, antibodies, receptor antagonists, ligands, antigens, antagonists, signal pathway cofactors, signal pathway components, pathogens, drugs, metabolites, and toxins.
In the method for monitoring a physiological or pathophysiological function, the tissue or cells may be implanted in an animal. The tissue or cells may also be incorporated into a device that is placed inside an animal. The method may be performed on any animal such as, for example, a mammal. Preferred mammals for use in the method include a mouse, rat, rabbit, pig, cat, dog, cattle, horse and sheep. Preferably, the mammal is a human.
The present invention further provides a method of regulating output of a signal, substance, or action to a subject. The method comprises placing within the subject, exogenous tissue or cells capable of carrying out a physiological or pathophysiological function, which tissue or cells can be used to monitor a chemical, physiological or pathophysiological variable associated with the physiological or pathophysiological function. The exogenous tissue or cells are coupled to an interventional device or a delivery device, and the output of a signal, substance, or action from the interventional or delivery device in response to the physiological or pathophysiological function of the exogenous tissue or cells, is regulated.
In response to the electrical or chemical signal, the delivery device delivers an electrical or mechanical stimuli. Alternatively, the delivery device delivers a drug or a compound. Preferably, the tissue or cells are excitable tissue or cells. Examples of excitable tissue or cells include cardiac tissue or cells and neuronal tissue or cells. A physiological or pathophysiological variable monitored may be e.g., heart rate regulation or heart rate dynamics. A chemical, physiological or pathophysiological variable may be e.g., a level of a compound such as blood glucose, insulin, thyroid hormone, clotting factors and components, endocrine hormone, paracrine hormone, autocrine hormone, antibody, receptor antagonists, ligands, antagonists, antigens, signal pathway cofactors, and signal pathway components, pathogens, drugs, metabolites, or toxins.
In accordance with a method of regulating the output of a signal to a subject, the exogenous tissue or cells may be implanted in a mammal. In an alternative embodiment, the tissue or cells may be incorporated into a device that is placed inside a mammal. The mammal may be selected from the group consisting of a mouse, rat, rabbit, pig, cat, dog, horse, cattle and a sheep. Preferably, the mammal is a human.
In still another aspect of the invention, there is provided a system for controlling heart function. The system comprises exogenous tissue or cells, capable of carrying out a physiological or pathophysiological function, placed within a subject; and an electrical connection placed between the exogenous tissue or cells and the natural pacemaker region of the heart. Preferably, excitable tissue or cells are used such as e.g., cardiac tissue or cells, or neuronal tissue or cells. If desired, an amplifier may be added to the system in order to boost the signal from the exogenous tissue or cells. In another embodiment of the system, the exogenous tissue or cells are connected to an electronic pacemaker. The exogenous tissue or cells may comprise cells that are molecularly, genetically, or cellularly engineered. A subject which may utilize the system for controlling heart function may be any animal. Preferably, the animal is a mammal. Examples of mammals which may utilize the system include but are not limited to a mouse, rat, rabbit, pig, cat, dog, cattle, horse or sheep. Most preferably, the mammal is human.